Our study reveals that the E2F1/FOXO1 complex suppresses retinoblastoma emergence by inducing cell death in the retina, in part through their combined transcriptional regulation of the retinal pro-apoptotic gene Bim. Because E2F1 and FOXO1 are not normally simultaneously functional in the nucleus, they require certain oncogenic stresses, such as loss of RB function, to trigger an apoptotic response and suppress tumor emergence. This evidence concerns the gene RB1 and retinoblastoma.